Abstract
Diversity in the genetic lesions that cause cancer is extreme. In consequence, a pressing challenge is the development of drugs that target patient-specific disease mechanisms. To address this challenge, we employed a chemistry-first discovery paradigm for de novo identification of druggable targets linked to robust patient selection hypotheses. In particular, a 200,000 compound diversity-oriented chemical library was profiled across a heavily annotated test-bed of >100 cellular models representative of the diverse and characteristic somatic lesions for lung cancer. This approach led to the delineation of 171 chemical-genetic associations, shedding light on the targetability of mechanistic vulnerabilities corresponding to a range of oncogenotypes present in patient populations lacking effective therapy. Chemically addressable addictions to ciliogenesis in TTC21B mutants and GLUT8-dependent serine biosynthesis in KRAS/KEAP1 double mutants are prominent examples. These observations indicate a wealth of actionable opportunities within the complex molecular etiology of cancer. Application of a chemistry-first approach matches chemicals with targetable, diverse genetic lesions and cancer-promoting mechanisms in human lung cancer, providing guidance for development of personalized cancer treatment.
Original language | English (US) |
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Pages (from-to) | 864-878.e29 |
Journal | Cell |
Volume | 173 |
Issue number | 4 |
DOIs | |
State | Published - May 3 2018 |
Keywords
- KRAS mutant
- NRF2 signaling
- cancer target identification
- chemical biology
- ciliogenesis
- glucocorticoid therapies
- lung cancer
- serine biosynthesis
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology